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研究生： 林芷蓉
Lin, Jhih-Rong
論文名稱： 探討周邊血粒線體DNA拷貝數在雙極症患者中所扮演的角色
Exploring the role of peripheral blood mitochondrial DNA copy number in bipolar patients
指導教授： 張惠華
Chang, Hui-Hua
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2021
畢業學年度： 109
語文別： 英文
論文頁數： 343
中文關鍵詞： 粒線體DNA拷貝數 、粒線體功能受損 、雙極症 、丙戊酸 、色胺酸代謝產物 、治療反應
外文關鍵詞： mitochondrial DNA copy number, mitochondrial dysfunction, bipolar disorder, valproate, tryptophan catabolites, treatment response
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    • 研究背景
    近期研究提出粒線體功能失衡會影響雙極症病理的假說。雙極症患者出現受損氧化磷酸化、異常能量改變及氧化壓力升高等現象。在細胞實驗中，丙戊酸會增進粒線體DNA拷貝數生成，而粒線體DNA拷貝數代表粒線體功能與生成的指標之一。然而，粒線體DNA拷貝數與雙極症和丙戊酸治療成效的關係仍未明確。此外，粒線體功能可能與色胺酸代謝產物有關。因此，本研究目標：(1)探討粒線體DNA拷貝數在雙極症患者和控制組是否有差異，尤其是使用丙戊酸的患者；(2)分析粒線體相關的核基因與環境壓力是否會影響粒線體DNA拷貝數；(3)分析雙極症患者粒線體DNA拷貝數與治療反應和臨床數值的關聯性，並進一步探討色胺酸代謝產物所扮演的角色。

    研究方法
    本研究為張惠華實驗室及其研究團隊從國立成功大學醫學院附設醫院招募符合DSM-5診斷標準的雙極症患者，並從社區招募排除精神相關共病的控制組。採集受試者空腹血糖偵測臨床數值 (包含粒線體DNA拷貝數、色胺酸代謝產物、血糖與發炎相關指標)，粒線體DNA拷貝數濃度用定量聚合酶連鎖反應檢測。本研究使用Alda量表來評估雙極症患者的丙戊酸治療反應。受試者會填寫童年時期創傷問卷與孤獨感問卷來評估社會心理壓力。此外，我們分析12個與粒線體DNA拷貝數相關的核基因進行基因分析。統計顯著值設於0.05。

    研究結果
    雙極症患者的粒線體DNA拷貝數高於控制組。其中服用丙戊酸的患者也有一致的結果，且丙戊酸的血中濃度與患者的粒線體DNA拷貝數呈現正相關。依丙戊酸的治療反應分組，發現治療反應佳的相較於治療反應差的患者有更高的粒線體DNA拷貝數。此外以信號接受特質曲線分析，以粒線體DNA拷貝數為2.05的數值時可區別丙戊酸治療反應的好壞(曲線下面積: 0.705; 95% 信賴區間: 0.560-0.851, p = 0.016)。此外，分析粒線體相關基因與社會心理壓力於粒線體DNA拷貝數的影響，我們發現POLG1與粒線體DNA拷貝數具相關性；在兒童時期創傷問卷中，疏忽身體照護與粒線體DNA拷貝數在病患與控制組皆呈現負相關，在控制組亦發現孤獨感與粒線體DNA拷貝數負相關趨勢。再者，臨床數值與粒線體DNA拷貝數的關聯性分析中發現：體重相關數值和C-反應蛋白濃度與雙極症患者的粒線體DNA拷貝數呈負相關；而血糖數值與控制組的粒線體DNA拷貝數呈正相關。此外，控制組的粒線體DNA拷貝數與瘦素呈現正相關，而雙極症患者則呈現負相關。然而，我們並未觀察到色胺酸代謝產物與粒線體DNA拷貝數的關聯性。

    結論
    本研究發現雙極症患者的粒線體DNA拷貝數高於控制組，而粒線體DNA拷貝數相關的基因與社會心理壓力可能會影響粒線體功能。此外，粒線體DNA拷貝數和丙戊酸濃度與治療成效有關聯，但並未與色胺酸代謝產物有關。我們的研究結果釐清粒線體DNA拷貝數在雙極症中所扮演的角色，並提供可能的治療策略。

    INTRODUCTION
    Recent studies have suggested the hypothesis of mitochondrial dysfunction in pathophysiology of bipolar disorder (BD). The evidence involved impaired oxidative phosphorylation, abnormal changing in energy, and increasing oxidative stress in BD patients. In cell line, valproate (VPA) increased the mitochondrial DNA copy number (MCN), a useful index of mitochondrial function and biogenesis. However, studies about the association among MCN, BD itself, and VPA treatment outcomes in BD patients remain unclear. In addition, mitochondrial function might be associated with tryptophan catabolites (TRYCAT). Therefore, the objectives of the study were (1) to compare the MCN levels in controls and BD, especially in VPA users; (2) to analyze the effects of mitochondria-related nuclear genes and psychosocial stress on MCN; (3) to explore the association between MCN, treatment response, and clinical indices in BD, and further to investigate the role of TRYCAT.

    MATERIALS AND METHODS
    Hui Hua Chang and her research team were responsible for recruiting the BD patients who met the DSM-5 criteria from National Cheng Kung University Hospital. We also enrolled the controls without psychiatric disorder history from community. Fasting blood samples were collected to detect clinical indices (including MCN, TRYCAT, sugar, and inflammatory indices). Quantitative polymerase chain reaction was used to measure MCN. Treatment response of VPA was using the Alda scale. Psychosocial stress was obtained from the Childhood Trauma Questionnaire (CTQ) and the UCLA loneliness scale. In addition, twelve candidate nuclear genes associated with MCN synthesis were genotyped and assessed. The level of significance was set at 0.05.

    RESULTS AND DISCUSSION
    Compared to controls, BD patients had significantly higher MCN levels. The result was still consistent in BD patients receiving VPA, and VPA concentration was positively correlated with MCN. When subgrouped BD patients by VPA responder or non-responder, MCN was significantly higher in VPA responder than non-responder. Furthermore, a receiver operating characteristic curve analysis suggested MCN level of 2.05 could discriminate between responder and non-responder (AUC: 0.705; 95% CI: 0.560-0.851, p = 0.016). In the analyses of mitochondria-related nuclear genes and psychosocial stress on MCN, we found that POLG1 was associated with MCN levels. The physical neglect domain of CTQ were negatively correlated with MCN in both BD and controls. The loneliness score was negatively correlated with MCN in controls. In the analyses of MCN and clinical indices in BD, MCN was significantly negatively correlated with weight profile and C-reactive protein in BD, and positively correlated with sugar profile in controls. MCN was significantly positively correlated with leptin in control, but negative in BD. However, we did not find the association between MCN and TRYCAT in BD.

    CONCLUSION
    Our findings indicated that BD had higher MCN levels than controls. MCN related genes and psychosocial stress might influence the mitochondrial function. Besides, MCN levels were associated with VPA concentration as well as treatment response, but not with TRYCAT. Our study helped to clarify the role of MCN in BD and provided insights into treatment approaches in the future.

    中文摘要 I Abstract III 致謝 V Contents VI List of Tables X List of Figures XVI List of Supplementary Appendix Tables XXII Abbreviation XXIV Chapter 1 Introduction 1 1.1 Bipolar disorder 1 1.1.1 Definition and epidemiology of bipolar disorder 1 1.1.2 Pharmacological management and treatment limitation in bipolar disorder 1 1.2 Mitochondrial DNA copy number (MCN) 3 1.2.1 Mitochondrial dysfunction hypothesis in bipolar disorder 3 1.2.2 Mitochondrial structure and physiology 3 1.2.3 MCN as an indicator of mitochondrial function 5 1.3 Tryptophan Catabolites (TRYCAT) 9 1.3.1 The role of tryptophan catabolites in bipolar disorder 9 1.3.2 General features of tryptophan catabolites 9 1.3.3 Association between mitochondrial function and tryptophan catabolites in mood disorder 10 Chapter 2 Objective of current study 13 Chapter 3 Material and Methods 14 3.2 Study design 14 3.3 Subjects 14 3.4 Clinical measurement 15 3.4.1 Disease assessment and hospitalizations 15 3.4.2 Adiposity and body fat distribution 15 3.4.3 Metabolic syndrome (MetS) assessments 15 3.4.4 Fasting lipid profiles 15 3.4.5 Fasting sugar profiles 16 3.4.6 Endocrine profile 16 3.4.7 Tryptophan catabolites 17 3.4.8 MCN in leukocytes 18 3.4.9 8-hydroxy-20-deoxyguanosine in leukocytes 18 3.4.10 Inflammatory biomarkers 18 3.4.11 Valproate serum concentration 19 3.4.12 Assessment of treatment response 19 3.4.13 Neurocognitive function assessment 20 3.4.14 SPECT with [99mTc] TRODAT-1 20 3.5 Genotype profile 21 3.5.1 DNA extraction 21 3.5.2 Whole-genome genotyping 21 3.5.3 Quality control 21 3.5.4 Haplotype block detection 22 3.6 Questionnaire 22 3.6.1 Childhood Trauma Questionnaire (CTQ) 22 3.6.2 Life Events Scale (LES) 22 3.6.3 World Health Organization Quality of Life (WHOQoL) 22 3.6.4 Pittsburgh Sleep Quality Index (PSQI) 23 3.6.5 The University of California, Los Angeles (UCLA) Loneliness Scale 23 3.6.6 Taiwan food craving inventory (TFCI) 23 3.7 Statistics 23 3.7.1 Clinical analysis 23 3.7.2 Genetic analysis 24 Chapter 4 Results 25 Part I: Mitochondrial function 25 4.1 Mitochondrial DNA copy number in controls and BD patients 25 4.1.1 Demographic and clinical characteristics of the controls and BD patients 25 4.1.2 Association between psychosocial stress and MCN in controls and BD patients 29 4.1.3 Genetic polymorphisms of MCN related nuclear gene in controls and BD patients 29 4.1.4 Correlation of MCN and clinical indices in controls and BD 31 4.2 Mitochondrial DNA copy number in controls and bipolar with VPA treatment 33 4.2.1 Demographic and clinical characteristics of the controls and BD patients with VPA treatment 33 4.2.2 Association between psychosocial stress and MCN in controls and BD patients with VPA treatment 36 4.2.3 Genetic polymorphisms of MCN related nuclear gene in controls and BD patients with VPA treatment 36 4.2.4 Correlation of MCN and clinical indices in BD patients with valproate treatment and controls 37 4.3 Treatment response in BD patients with VPA treatment 40 4.3.1 Demographic and clinical characteristics of the VPA responder and non-responder 40 4.3.2 Correlation of VPA treatment response and clinical indices 41 4.3.3 ROC curve of MCN to discriminate between VPA responder and non-responder 43 4.4 Mitochondrial DNA copy number in BD I and BD II patients with VPA treatment 44 4.4.1 Demographic and clinical characteristics of BD I and BD II with VPA treatment 44 4.4.2 Correlation of MCN and clinical indices in BD I and BD II patients with VPA treatment 46 4.5 Mitochondrial DNA copy number in BD patients with and without metabolic syndrome 48 4.5.1 Demographic and clinical characteristics of BD with and without metabolic syndrome 48 4.5.2 Correlation of MCN and clinical indices in BD with and without metabolic syndrome 50 Part II: Tryptophan catabolites 52 4.6 Tryptophan catabolites in controls and BD patients 52 4.6.1 Demographic and clinical characteristics of the controls and BD patients 52 4.6.2 Genetic polymorphisms of tryptophan catabolites related genes in controls and BD patients 54 4.6.3 Correlation of tryptophan catabolites and clinical indices in controls and BD 56 4.7 Tryptophan catabolites in controls and BD patients with VPA treatment 59 4.7.1 Demographic and clinical characteristics of the controls and BD patient with VPA treatment 59 4.7.2 Genetic polymorphisms of tryptophan catabolites related genes in controls and BD patients with VPA treatment 61 4.7.3 Correlation of tryptophan catabolites and clinical indices in controls and BD with VPA treatment 63 Chapter 5 Discussion 280 5.1 Mitochondrial DNA copy number in BD patients 280 5.1.1 Roles of MCN in BD patients 280 5.1.2 Effects of medication on mitochondria 281 5.1.3 The association between psychosocial stress and mitochondrial function in BD 282 5.1.4 Genetics for mitochondrial dysfunction in bipolar disorder 283 5.1.5 MCN might be a potential biomarker to distinguish treatment responder and non-responder 286 5.1.6 Diagnostic subtype of BD and mitochondrial function 286 5.1.7 Metabolic syndrome and mitochondrial dysfunction in BD 287 5.2 Correlation of MCN and clinical indices 288 5.2.1 Metabolic indices 288 5.2.2 Cognitive function 288 5.2.3 Disease severity and treatment response 289 5.2.4 Striatal DAT availability 289 5.2.5 Endocrine profile 290 5.2.6 Inflammatory profile 290 5.2.7 Subject reported outcome 291 5.3 The role of tryptophan catabolites in BD patients 292 5.3.1 Tryptophan catabolites alteration in BD patients 292 5.3.2 The association between mitochondrial function and TRYCAT 294 5.3.3 The association between TRYCAT and treatment response 295 5.3.4 The association between TRYCAT and inflammation 295 5.3.5 The association between TRYCAT and cognitive function 295 5.3.6 The association between TRYCAT and FGF2 296 5.3.7 The association between TRYCAT and food craving 297 5.4 Clinical implication of this study 299 5.5 Limitation 300 Chapter 6 Conclusion 301 Chapter 7 Reference 302

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